Hereditary Nonpolyposis Colorectal Cancer

No Results

No Results

processing….

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. It is inherited as an autosomal dominant syndrome as a result of defective mismatch repair (MMR) proteins. HNPCC, accounts for 2-5% of all colorectal carcinomas. Over 90% of all colorectal cancers in HNPCC patients demonstrate a high microsatellite instability (MSI-H), which means at least 2 or more genes have been mutated in HNPCC families or atypical HNPCC families.

Colorectal cancer in patients with HNPCC presents at an earlier age than in the general population and is characterized by an increased risk of other cancers, such as endometrial cancer and, to a lesser extent, cancers of the ovary, stomach, small intestine, hepatobiliary tract, pancreas, upper urinary tract, prostrate, brain, and skin.

HNPCC is divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (HNPCC associated with other cancers of the gastrointestinal [GI] or reproductive system). The increased cancer risk is due to inherited mutations that degrade the self-repair capability of DNA.

The tumor testing (ie, immunohistochemistry, MSI, germline testing, and BRAF mutation testing), screening, and prophylactic surgery all help to reduce the risk of death in patients with HNPCC or Lynch syndrome.

The benefits of all strategies primarily affect relatives with a mutation associated with HNPCC or Lynch syndrome.

The widespread implementation of colorectal tumor testing helps to identify families with HNPCC or Lynch syndrome.

Colorectal tumor testing could yield substantial benefits at acceptable cost. Particularly in females with a mutation associated with HNPCC or Lynch syndrome who begin regular screening and have reducing surgery. The cost-effectiveness of such testing depends on a particular rate in relatives at risk for HNPCC or Lynch syndrome.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. It is inherited as an autosomal dominant syndrome (see the image below), as a result of defective mismatch repair (MMR) proteins. HNPCC accounts for 2-5% of all colorectal carcinomas. Over 90% of all colorectal cancers in HNPCC patients demonstrate a high microsatellite instability (MSI-H), which means at least 2 or more genes have been mutated in HNPCC families or atypical HNPCC families.

See Benign or Malignant: Can You Identify These Colonic Lesions?, a Critical Images slideshow, to help identify the features of benign lesions as well as those with malignant potential.

Colorectal cancer in patients with HNPCC presents at an earlier age than in the general population and is characterized by an increased risk of other cancers, such as endometrial cancer and, to a lesser extent, cancers of the ovary, stomach, small intestine, hepatobiliary tract, pancreas, upper urinary tract, prostrate, brain, and skin.

HNPCC is divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (HNPCC associated with other cancers of the gastrointestinal [GI] or reproductive system). The increased cancer risk is due to inherited mutations that degrade the self-repair capability of DNA.

Lynch syndrome was named after Dr. Henry T. Lynch. In 1966, Dr. Lynch and colleagues described familial aggregation of colorectal cancer with stomach and endometrial tumors in 2 extended kindreds and named it cancer family syndrome. The authors later termed this constellation Lynch syndrome, and, more recently, this condition has been called HNPCC.

Before molecular genetic diagnostics became available in the 1990s, a comprehensive family history was the only basis from which to estimate the familial risk of colorectal cancer.

For patient education resources, see Cancer Center, as well as Colon Cancer and Rectal Cancer.

In hereditary nonpolyposis colorectal cancer (HNPCC), an inherited mutation in one of the DNA mismatch repair (MMR) genes appears to be a critical factor. MMR genes normally produce proteins that identify and correct sequence mismatches that may occur during DNA replication. In HNPCC, a mutation that inactivates an MMR gene leads to the accumulation of cell mutations and greatly increases the likelihood of malignant transformation and cancer.

Researchers have identified 7 distinct MMR genes, including the following:

hMLH1 on band 3p22

hMSH2 and hMSH6 on band 2p16

hPMS1 on band 3p32 and hPMS2 on band 7q22

Other mutations include hMSH3 on band 5q14.1 and EXO1 on band 1q43. Mutations of hMLH1 and hMSH2 account for nearly 70% of MMR mutations in HNPCC; 10% involve hMSH6. The genes responsible for the remaining 20-25% of cases have not yet been discovered.

Table 1. Seven different genes are known to be associated with HNPCC, and all of them are involved with DNA mismatch repair, identified with the frequencies below. (Open Table in a new window)

Mismatch Excision Repaired MMR

Chromosome Location

Frequency of HNPCC Cases

MSH2

2p16

45-50%

MLH1

3p22.3/A>

20%

MSH6

2p16

10%

PMS2

7p22.1

1%

PMS1

2q32.2

Rare

MSH3

5q14.1

Rare

EXO1

1q43

Rare

Other genes not yet discovered

20-25%

Germline mutations are often inherited but may also arise spontaneously or de novo in a new generation. These patients are often identified only after they develop colon cancer early in life. Transmission is autosomal dominant (see image below), meaning that 50% of the offspring of affected individuals inherit a mutant allele.

Because phenotypic expression of HNPCC requires inactivation of both alleles, germline mutations of one allele must be accompanied by somatic inactivation of the wild-type allele. Inactivation may result from deletions, mutations, or splicing errors occurring anywhere throughout the gene. Mutations that lead to protein truncation account for most inactivating hMLH1 and hMSH2 mutations. Failure to correct replication errors results in genomic instability.

Despite the absence of polyposis, HNPCC-associated colorectal cancers are believed to arise from preexisting discrete proximal colonic adenomas. Affected individuals have a propensity to develop predominantly right-sided, flat adenomas at a young age. Patients with Lynch syndrome or HNPCC develop adenomas at the same rate as individuals in the general population; however, the adenomas in those with Lynch syndrome or HNPCC are more likely to progress to cancer. Carcinogenesis progresses more rapidly in these patients (in 2-3 y) than in patients with sporadic adenomas (8-10 y).

Synchronous colorectal tumors (primary tumors diagnosed within 6 mo of each other) and metachronous colorectal tumors (primary tumors occurring more than 6 mo apart) are more common in persons with HNPCC. An individual with an HNPCC mutation who does not undergo a partial or total colectomy after the first mass is diagnosed as malignant has an estimated 30-40% risk of developing a metachronous tumor within 10 years and a 50% risk within 15 years. In the general population, the risk is 3% in 10 years and 5% within 15 years.

The incidence of hereditary nonpolyposis colorectal cancer (HNPCC) in the United States is 2-5%, or 7500 new occurrences of HNPCC annually.

Large geographic differences are observed in the occurrence of hereditary nonpolyposis colorectal cancer (HNPCC).

Colorectal cancer in persons with hereditary nonpolyposis colorectal cancer (HNPCC) occurs at an earlier age than in the general population. In persons with HNPCC, the average age of polyp onset is in the late second decade and early third decade of life. The average age of colorectal cancer onset is 44 years in members of families that meet the Amsterdam criteria compared with age 60-65 years in the general population (see History, Guidelines).

Lynch syndrome has no known racial proclivity; however, ethnic-specific mutations have been observed in the Finnish and Swedish populations. Colorectal cancer rates in the Ashkenazi Jewish population are disproportionately high, possibly the highest of any ethnic group worldwide. Although neither hereditary nonpolyposis colorectal cancer (HNPCC) nor classic FAP are more common in Ashkenazim than in the general population, both have a connection to individuals of Ashkenazi Jewish heritage.

A specific mutation in the MSH2 gene, G1906K, is found in 2-3% of all colorectal cancers in Ashkenazi Jews younger than 60 years. One third of Ashkenazi Jewish individuals who meet the criteria for genetic testing of HNPCC have this mutation. This mutation is rarely found in the general population but is more common in young Ashkenazi Jews with colorectal cancer. In individuals in whom colorectal cancer is diagnosed at age 40 years or younger, 7% have been found to carry this mutation. Conversely, the mutation is found in less than 1% of Ashkenazim persons in whom colorectal cancer is diagnosed after age 60 years.

Contrary to American and European reports, gastric cancer may be more common than endometrial cancer in the Asian (Japanese, Korean, Chinese) population.

Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly diagnosed in both men and women.

The 5-year survival rate in patients with hereditary nonpolyposis colorectal cancer (HNPCC) is estimated to be approximately 60%, compared with 40-50% for sporadic cases. Colorectal tumors that are microsatellite instability (MSI)-positive have distinctive features, including a tendency to arise in the proximal colon, lymphocytic infiltrated, and a poorly differentiated, mucinous or signet ring appearance. ^[1]  Investigators have found that MSI-positive tumors are associated with improved survival rates. ^{[2, 3, 4, 5, 6]}

When compared based on stage, patients with colorectal cancer from families with a history of HNPCC have a better prognosis than patients with colorectal cancer in the general population (sporadic colon cancer), which may be explained by immunologic factors. Immunologic studies in mice with colon cancer have demonstrated that tumors influence host immune response by altering host T-cell receptors. ^[7]  However, the defective T-cell response was observed only in animals with long-standing tumors, implying that rapid tumor growth, as seen in HNPCC, may preserve immune response. ^[7]  This hypothesis merits further investigation.

The best evidence that colonoscopic screening is beneficial for preventing colon cancer in patients with HNPCC has come from observational studies of 22 HNPCC families that were followed for 15 years. ^{[8, 9]}  One hundred and thirty-three family members were voluntarily screened every 3 years, and 119 declined colonoscopic surveillance during the study period.

Colorectal cancer was reduced by 62% in the screened group versus the unscreened group. The reduction was ascribed to polypectomies in the intervention group. No colorectal cancer-related deaths occurred in the group that underwent regular colonoscopic screening compared with a 36% colorectal cancer-related mortality rate in the unscreened group.

Colon cancers that occur in patients with HNPCC are believed to arise from adenomas; however, these adenomatous polyps likely have a shortened adenoma-carcinoma progression sequence compared with the general population. Thus, for a known MLH1 or MSH2 germline mutation carrier, a full colonoscopy every 1-2 years beginning at ages 20-25 years or 5 years before the first diagnosed colorectal cancer in the family is recommended. After the age of 35-40 years, colonoscopy should be performed annually.

The implementation of colorectal tumor testing to identify families with HNPCC or Lynch syndrome could yield substantial benefits at acceptable cost, particularly in females with a mutation associated with HNPCC or Lynch syndrome who begin regular screening and have prophylactic surgery. The cost-effectiveness of such testing depends on a particular rate among relatives at risk for HNPCC or Lynch syndrome. ^[10]

Although not everyone who inherits the gene for HNPCC develops colorectal cancer, individuals with Lynch syndrome have a 70-80% lifetime risk of developing colon cancer. Of these cancers, two thirds occur in the proximal colon (proximal to the splenic flexure). In approximately 45% of affected individuals, multiple synchronous and metachronous colorectal may occur within 10 years of resection.

Other cancers associated with HNPCC include the following:

Endometrial cancer: The lifetime risk is 30-40% by age 70 years. The average age at diagnosis is 46 years. Half of the patients with both colon and endometrial cancer present with endometrial cancer first.

Ovarian cancer: The lifetime risk is 9-12% by age 70 years. The average age at diagnosis is 42.5 years. Approximately 30% of these tumors present before age 40 years.

Gastric cancer: The lifetime risk is around 13% (higher in Asians). The mean age at diagnosis of gastric cancer is 56 years; intestinal-type adenocarcinoma is the most commonly reported pathology, especially in Asian countries such as Japan, Korea, and China.

Transitional cell carcinoma: The lifetime risk is 4-10%. This principally affects the upper urinary tract (ureters and renal pelvis). Certain group of patients (eg, those with HNPCC with MSH2 mutations) are at an increased risk not only for upper urinary tract tumors but also for bladder cancer.

Adenocarcinoma of the small bowel: The lifetime risk is 1-3%. These occur most commonly in the duodenum and jejunum.

Glioblastoma: The lifetime risk is 1-4%. Also known as Turcot syndrome, this is a variant of HNPCC (see below).

Malignancies of the larynx, breast, prostate, liver, biliary tree, pancreas, and the hematopoietic system are more common in patients with HNPCC.

Table 2. Incidence of different types of cancers in individuals with Lynch syndrome and those in the general population. (Open Table in a new window)

Type of Cancer

General Population Risk (by age 70 y)

Lynch Syndrome Risk (by age 70 y)

Endometrial

1.5%

30-40%

Ovarian

1%

9-12%

Upper Urinary Tract*

Less than 1%

4-10%

Stomach

Less than 1%

13% (higher in Asians)

Small Bowel

Less than 1%

1-3%

Brain

Less than 1%

1-4%

Biliary Tract

Less than 1%

1-5%

* Those with HNPCC with MSH2 mutations are at an increased risk not only for upper urinary tract tumors but also for bladder cancer.

Turcot syndrome

Formerly considered a separate disorder from familial adenomatosis polyposis (FAP), Turcot syndrome is clinically characterized by both multiple colorectal adenomas and primary brain tumor. In 1995, Hamilton et al demonstrated that this association may result from at least 2 distinct types of germline defects: a mutation in the APC gene (which represents two thirds of cases and is responsible for FAP) and a mutation in mismatch repair (MMR) gene PMS2 or MLH1 (which represents one third of cases). ^[11]  Medulloblastoma is most common with APC mutations, whereas glioblastoma is most common with MMR gene mutations.

Muir-Torre syndrome

This is a type or variant of HNPCC and is characterized by a mutation in MSH2 and/or MLH1 genes, although some cases have been described with mutations in the MSH6 gene. Muir-Torre syndrome accounts for much less than 1% of all hereditary colorectal cancer cases and is characterized by the typical features of HNPCC and increased risk of developing sebaceous gland tumors, such as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas. ^[12]

IMPACC is a national support network founded in 1986 to help patients and families dealing with familial polyposis and hereditary colon cancer. It provides information and referrals, encourages research, and educates professionals and public. Phone support network, correspondence, and literature are available.

Intestinal Multiple Polyposis and Colorectal Cancer

PO Box 11

Conyngham, PA 18219

Phone: 570-788-3712

Fax: 717-788-1818

E-mail: impacc@epix.net 

The ACS provides assistance to those with cancer. Check the telephone directory for your local chapter.

American Cancer Society

National Home Office

250 Williams St NW

Atlanta, GA 30303

Phone: 1-800-227-2345

Website: http://www.cancer.org/

In addition to offering information, the ACS has a number of educational programs and informational materials. Call the ACS for information regarding their local chapters.

The CGA-ICC was established in 1995 “to improve understanding of the basic science of inherited colorectal cancer and the clinical management of affected families.” The CGA-ICC’s focus is to provide education to professionals and patients, access to clinical and chemoprevention trials, resources for developing new genetic registers, and a forum for collaborative research.

Collaborative Group of the Americas on Inherited Colorectal Cancer

Dr. James Church

Director, David G Jagelman

Colorectal Cancer Registries

Cleveland Clinic Foundation

Department of Colorectal Surgery

9500 Euclid Avenue, Desk A30

Cleveland OH 44195

Phone: 216-444-3540

Website: http://www.cgaicc.com/

The JHHCCR provides education and information about hereditary colorectal cancer.

Johns Hopkins Hereditary Colorectal Cancer Registry

Phone: 410-955-3875; 1-888-77-COLON (1-888-772-6566)

E-mail: hccregistry@jhmi.edu

Website: http://www.hopkinsmedicine.org/kimmel_cancer_center/centers/colorectal.html

The NCI is the US government’s principal agency for cancer research. A live help line in English (https://livehelp.cancer.gov) or Spanish (http://livehelp-es.cancer.gov) is open Monday through Friday, 8:00 am to 11:00 pm Eastern Standard Time, and offers free information on all aspects of cancer. Information on clinical trials is available at http://www.cancer.gov/clinicaltrials/ .

National Cancer Institute

Information Service (CIS)

BG 9609 MSC 9760

9609 Medical Center Drive

Bethesda, MD 20892-9760

Phone: 1-800-4-CANCER (1-800-422-6237) (Monday to Friday, 8 am to 8 pm Eastern Standard Time)

Website: http://www.cancer.gov/

E-mail: https://www.cancer.gov/contact/email-us

Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010 Jun. 138 (6):2073-87.e3. [Medline].

Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun. 116 (6):1453-6. [Medline].

Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010 Jun. 138 (6):2073-87.e3. [Medline].

Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 2010 Mar. 7 (3):153-62. [Medline].

Ismael NE, El Sheikh SA, Talaat SM, Salem EM. Mismatch repair proteins and microsatellite instability in colorectal carcinoma (MLH1, MSH2, MSH6 and PMS2): histopathological and immunohistochemical study. Open Access Maced J Med Sci. 2017 Mar 15. 5 (1):9-13. [Medline].

Chen W, Swanson BJ, Frankel WL. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagn Pathol. 2017 Mar 4. 12 (1):24. [Medline].

Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992 Dec 11. 258 (5089):1795-8. [Medline].

Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995 Dec 20. 64 (6):430-3. [Medline].

Houlston RS, Murday V, Harocopos C, Williams CB, Slack J. Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic. BMJ. 1990 Aug 18-25. 301 (6748):366-8. [Medline]. [Full Text].

Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med. 2011 Jul 19. 155 (2):69-79. [Medline].

Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot’s syndrome. N Engl J Med. 1995 Mar 30. 332 (13):839-47. [Medline]. [Full Text].

Bhaijee F, Brown AS. Muir-Torre syndrome. Arch Pathol Lab Med. 2014 Dec. 138 (12):1685-9. [Medline].

American Cancer Society. Genetic testing, screening, and prevention for people with a strong family history of colorectal cancer. Available at https://www.cancer.org/content/cancer/en/cancer/colon-rectal-cancer/causes-risks-prevention/genetic-tests-screening-prevention.html. Revised: March 2, 2017; Accessed: March 22, 2017.

Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18. 96 (4):261-8. [Medline]. [Full Text].

[Guideline] Syngal S, Brand RE, Church JM, et al, for the American College of Gastroenterology. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb. 110 (2):223-62; quiz 263. [Medline].

Lothe RA, Peltomäki P, Meling GI, et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993 Dec 15. 53 (24):5849-52. [Medline].

Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst. 1995 Aug 2. 87 (15):1114-25. [Medline].

Dunlop MG, Farrington SM, Carothers AD, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 1997 Jan. 6 (1):105-10. [Medline]. [Full Text].

American Cancer Society. Cancer facts & figures 2017. Atlanta, Ga: American Cancer Society; 2017. Available at https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Accessed: March 23, 2017.

[Guideline] Levin B, Lieberman DA, McFarland B, et al, for the American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008 May. 134(5):1570-95. [Medline].

Giraldez MD, Balaguer F, Bujanda L, et al. MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. Clin Cancer Res. 2010 Nov 15. 16 (22):5402-13. [Medline].

American Cancer Society. American Cancer Society recommendations for colorectal cancer early detection. Available at https://www.cancer.org/cancer/colon-rectal-cancer/detection-diagnosis-staging/acs-recommendations.html. Revised: March 1, 2017; Accessed: March 22, 2017.

American Cancer Society. Colorectal cancer screening tests. Available at https://www.cancer.org/cancer/colon-rectal-cancer/detection-diagnosis-staging/screening-tests-used.html. Revised: March 2, 2017; Accessed: March 22, 2017.

Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute Workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. 1997 Dec 3. 89 (23):1758-62. [Medline]. [Full Text].

Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part II. The utility of microsatellite instability testing. J Mol Diagn. 2008 Jul. 10 (4):301-7. [Medline]. [Full Text].

Weissman SM, Bellcross C, Bittner CC, et al. Genetic counseling considerations in the evaluation of families for Lynch syndrome–a review. J Genet Couns. 2011 Feb. 20 (1):5-19. [Medline].

Vasen HF, Nagengast FM, Griffioen G, et al for the Work Group ‘Hereditary non-polyposis- colon-rectum cancers’. [Periodic colonoscopic examinations of persons with a positive family history for colorectal cancer. Work Group ‘Hereditary non-polyposis- colon-rectum cancers’] [Dutch]. Ned Tijdschr Geneeskd. 1999 Jun 5. 143 (23):1211-4. [Medline].

[Guideline] Smith RA, von Eschenbach AC, Wender R, et al, for the ACS Prostate Cancer Advisory Committee, ACS Colorectal Cancer Advisory Committee, et al. American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001–testing for early lung cancer detection. CA Cancer J Clin. 2001 Jan-Feb. 51(1):38-75; quiz 77-80. [Medline]. [Full Text].

[Guideline] Winawer S, Fletcher R, Rex D, et al, for the Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology. 2003 Feb. 124(2):544-60. [Medline].

Love RR, Morrissey JF. Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med. 1984 Nov. 144 (11):2209-11. [Medline].

Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991 May. 34 (5):424-5. [Medline].

Mecklin JP, Järvinen HJ, Peltokallio P. Cancer family syndrome. Genetic analysis of 22 Finnish kindreds. Gastroenterology. 1986 Feb. 90 (2):328-33. [Medline].

[Guideline] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): colorectal cancer screening. V 2.2016. Available at https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed: March 23, 2017.

Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006 Sep 27. 296 (12):1507-17. [Medline].

Ramsoekh D, Wagner A, van Leerdam ME, et al. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hered Cancer Clin Pract. 2009 Dec 23. 7 (1):17. [Medline]. [Full Text].

Bonadona V, Bonaiti B, Olschwang S, et al, for the French Cancer Genetics Network. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011 Jun 8. 305 (22):2304-10. [Medline].

National Cancer Institute. Genetics of colorectal cancer (PDQ)–health professional version. Available at https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq. Updated: March 16, 2017; Accessed: March 22, 2017.

Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006 Aug 1. 66 (15):7810-7. [Medline]. [Full Text].

Renkonen-Sinisalo L, Sipponen P, Aarnio M, et al. No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol. 2002 May. 37 (5):574-7. [Medline].

Ramsey SD. Screening for the Lynch syndrome. N Engl J Med. 2005 Aug 4. 353 (5):524-5; author reply 524-5. [Medline].

Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005 May 5. 352 (18):1851-60. [Medline]. [Full Text].

Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993 Feb 1. 71 (3):677-85. [Medline].

Bliss CM Jr, Schroy PC 3rd. Endoscopic diagnosis and management of hereditary nonpolyposis colorectal cancer. Curr Opin Gastroenterol. 2004 Sep. 20 (5):468-73. [Medline].

Foster JH. Survival after liver resection for cancer. Cancer. 1970 Sep. 26 (3):493-502. [Medline].

Exelby PR, Filler RM, Grosfeld JL. Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey–1974. J Pediatr Surg. 1975 Jun. 10 (3):329-37. [Medline].

Weinberger JM, Cohen Z, Berk T. Polyposis coli preceded by hepatocellular carcinoma: report of a case. Dis Colon Rectum. 1981 May-Jun. 24 (4):296-300. [Medline].

Lanspa SJ, Jenkins JX, Cavalieri RJ, et al. Surveillance in Lynch syndrome: how aggressive?. Am J Gastroenterol. 1994 Nov. 89 (11):1978-80. [Medline].

de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G, et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum. 2002 Dec. 45 (12):1588-94. [Medline].

Syngal S, Weeks JC, Schrag D, Garber JE, Kuntz KM. Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations. Ann Intern Med. 1998 Nov 15. 129 (10):787-96. [Medline]. [Full Text].

Stupart DA, Goldberg PA, Baigrie RJ, Algar U, Ramesar R. Surgery for colonic cancer in HNPCC: total vs segmental colectomy. Colorectal Dis. 2011 Dec. 13 (12):1395-9. [Medline].

Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet Oncol. 2002 Mar. 3 (3):166-74. [Medline].

O’Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res. 2002 Feb. 8 (2):314-46. [Medline]. [Full Text].

DuBois RN, Smalley WE. Cyclooxygenase, NSAIDs, and colorectal cancer. J Gastroenterol. 1996 Dec. 31 (6):898-906. [Medline].

Sinicrope FA, Half E, Morris JS, et al, Familial Adenomatous Polyposis Study Group. Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients. Cancer Epidemiol Biomarkers Prev. 2004 Jun. 13 (6):920-7. [Medline]. [Full Text].

Markowitz SD. Aspirin and colon cancer–targeting prevention?. N Engl J Med. 2007 May 24. 356 (21):2195-8. [Medline].

Burn J, Gerdes AM, Macrae F, et al, for the, CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011 Dec 17. 378 (9809):2081-7. [Medline]. [Full Text].

Cole BF, Baron JA, Sandler RS, et al, for the Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6. 297 (21):2351-9. [Medline]. [Full Text].

Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Intern Med. 1998 Oct 1. 129 (7):517-24. [Medline]. [Full Text].

Baron JA, Beach M, Mandel JS, et al, for the Calcium Polyp Prevention Study Group. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med. 1999 Jan 14. 340 (2):101-7. [Medline]. [Full Text].

Grau MV, Baron JA, Sandler RS, et al. Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst. 2003 Dec 3. 95 (23):1765-71. [Medline]. [Full Text].

Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL. Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst. 2002 Mar 20. 94 (6):437-46. [Medline]. [Full Text].

Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al, for the Women’s Health Initiative Investigators. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med. 2004 Mar 4. 350 (10):991-1004. [Medline]. [Full Text].

Chlebowski RT, Anderson GL. Menopausal hormone therapy and cancer: changing clinical observations of target site specificity. Steroids. 2014 Nov. 90:53-9. [Medline].

Slattery ML, Caan BJ, Potter JD, et al. Dietary energy sources and colon cancer risk. Am J Epidemiol. 1997 Feb 1. 145 (3):199-210. [Medline]. [Full Text].

Colangelo LA, Gapstur SM, Gann PH, Dyer AR. Cigarette smoking and colorectal carcinoma mortality in a cohort with long-term follow-up. Cancer. 2004 Jan 15. 100 (2):288-93. [Medline]. [Full Text].

Nilsen TI, Vatten LJ. Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br J Cancer. 2001 Feb 2. 84 (3):417-22. [Medline]. [Full Text].

Agiannidis C, Pana ZD, Molyva D, Kalokasidis K, Mixiou M. Metachronous occurrence of colorectal cancer in a Muir-Torre syndrome patient presenting with recurrent sebaceous adenoma of the eyelid: case report and updated review of the literature. J Cutan Med Surg. 2012 Nov-Dec. 16 (6):394-9. [Medline].

Brixen LM, Bernstein IT, Bülow S, Ehrnrooth E. Survival of patients with Stage III colon cancer is improved in hereditary non-polyposis colorectal cancer compared with sporadic cases. A Danish registry based study. Colorectal Dis. 2013 Jul. 15 (7):816-23. [Medline].

Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994 Mar 17. 368 (6468):258-61. [Medline].

Burn J, Mathers J, Bishop DT. Genetics, inheritance and strategies for prevention in populations at high risk of colorectal cancer (CRC). Recent Results Cancer Res. 2013. 191:157-83. [Medline].

Calistri D, Presciuttini S, Buonsanti G, et al. Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition. Int J Cancer. 2000 Jan 20. 89 (1):87-91. [Medline]. [Full Text].

Church JM. Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann Med. 1996 Dec. 28 (6):479-82. [Medline].

Cummings JH, Bingham SA. Diet and the prevention of cancer. BMJ. 1998 Dec 12. 317 (7173):1636-40. [Medline]. [Full Text].

Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, Pa: Saunders Elsevier; 2006.

Heiskanen I, Jarvinen HJ. Fate of the rectal stump after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Int J Colorectal Dis. 1997. 12 (1):9-13. [Medline].

Hendriks YM, de Jong AE, Morreau H, et al. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin. 2006 Jul-Aug. 56 (4):213-25. [Medline]. [Full Text].

Jarvinen TA, Pelto-Huikko M, Holli K, Isola J. Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol. 2000 Jan. 156 (1):29-35. [Medline]. [Full Text].

Kacerovska D, Cerna K, Martinek P, et al. MSH6 mutation in a family affected by Muir-Torre syndrome. Am J Dermatopathol. 2012 Aug. 34 (6):648-52. [Medline].

Lanspa SJ, Jenkins JX, Watson P, et al. Natural history of at-risk Lynch syndrome family members with respect to adenomas. Nebr Med J. 1992 Nov. 77 (11):310-3. [Medline].

Lin KM, Shashidharan M, Ternent CA, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 Apr. 41 (4):428-33. [Medline].

Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006 Sep 27. 296 (12):1507-17. [Medline]. [Full Text].

Lynch HT. Is there a role for prophylactic subtotal colectomy among hereditary nonpolyposis colorectal cancer germline mutation carriers?. Dis Colon Rectum. 1996 Jan. 39 (1):109-10. [Medline].

Lynch HT, Boland CR, Gong G, et al. Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications. Eur J Hum Genet. 2006 Apr. 14 (4):390-402. [Medline]. [Full Text].

Lynch HT, Krush AJ. Cancer family “G” revisited: 1895-1970. Cancer. 1971 Jun. 27 (6):1505-11. [Medline].

Lynch HT, Riley BD, Weissman SM, et al. Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: Problems in diagnosis, surveillance, and management. Cancer. 2004 Jan 1. 100 (1):53-64. [Medline]. [Full Text].

Mizoguchi T, Yamada K, Furukawa T, et al. Expression of the MDR1 gene in human gastric and colorectal carcinomas. J Natl Cancer Inst. 1990 Nov 7. 82 (21):1679-83. [Medline].

Nugent KP, Spigelman AD, Phillips RK. Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Dis Colon Rectum. 1993 Nov. 36 (11):1059-62. [Medline].

Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006 Jan 19. 354 (3):261-9. [Medline]. [Full Text].

Macaron C, Leach BH, Burke CA. Hereditary colorectal cancer syndromes and genetic testing. J Surg Oncol. 2015 Jan. 111 (1):103-11. [Medline].

Kalady MF, Heald B. Diagnostic approach to hereditary colorectal cancer syndromes. Clin Colon Rectal Surg. 2015 Dec. 28 (4):205-14. [Medline].

Lindberg LJ, Ladelund S, Frederiksen BL, Smith-Hansen L, Bernstein I. Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance. J Med Genet. 2016 Dec 30. [Medline].

Shawki S, Kalady MF. Recent advances in understanding Lynch syndrome. F1000Res. 2016 Dec 21. 5:2889. [Medline].

Chen CH, Sheng Jiang S, et al. DNA methylation identifies loci distinguishing hereditary nonpolyposis colorectal cancer without germ-line MLH1/MSH2 mutation from sporadic colorectal cancer. Clin Transl Gastroenterol. 2016 Dec 15. 7 (12):e208. [Medline].

Gelsomino F, Barbolini M, Spallanzani A, Pugliese G, Cascinu S. The evolving role of microsatellite instability in colorectal cancer: a review. Cancer Treat Rev. 2016 Dec. 51:19-26. [Medline].

Rohlin A, Rambech E, Kvist A, et al. Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. Fam Cancer. 2017 Apr. 16 (2):195-203. [Medline].

Moller P, Seppala T, Bernstein I, et al, for the Mallorca Group. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017 Mar. 66 (3):464-72. [Medline].

Guivatchian T, Koeppe ES, Baker JR, et al. Family history in colonoscopy patients: feasibility and performance of electronic and paper-based surveys for colorectal cancer risk assessment in the outpatient setting. Gastrointest Endosc. 2017 Feb 4. [Medline].

Gould-Suarez M, El-Serag HB, Musher B, Franco LM, Chen GJ. Cost-effectiveness and diagnostic effectiveness analyses of multiple algorithms for the diagnosis of Lynch syndrome. Dig Dis Sci. 2014 Dec. 59 (12):2913-26. [Medline].

Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology. 2014 Mar. 146 (3):643-6.e8. [Medline].

Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, for the Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014 Jan. 16 (1):101-16. [Medline].

[Guideline] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): genetic/familial high-risk assessment: colorectal. V 2.2016. Available at https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed: March 23, 2017.

Mismatch Excision Repaired MMR

Chromosome Location

Frequency of HNPCC Cases

MSH2

2p16

45-50%

MLH1

3p22.3/A>

20%

MSH6

2p16

10%

PMS2

7p22.1

1%

PMS1

2q32.2

Rare

MSH3

5q14.1

Rare

EXO1

1q43

Rare

Other genes not yet discovered

20-25%

Type of Cancer

General Population Risk (by age 70 y)

Lynch Syndrome Risk (by age 70 y)

Endometrial

1.5%

30-40%

Ovarian

1%

9-12%

Upper Urinary Tract*

Less than 1%

4-10%

Stomach

Less than 1%

13% (higher in Asians)

Small Bowel

Less than 1%

1-3%

Brain

Less than 1%

1-4%

Biliary Tract

Less than 1%

1-5%

MMR Mutations

Protein Staining

MLH1

MSH2

MSH6

PMS2

MLH1

–

+

+

+

MSH2

+

–

–

+

MSH6

+

+

–

+

PMS2

+

+

+

–

Surveillance

MLH1, MSH2, MSH6 (males)

MSHG (females)

Colon

Colonoscopy, every 1-2 years, starting at age 20-25 years

Colonoscopy, every 1-2 years, starting at age 30 years

Endometrium

Ultrasonography and CA-125, every 1-2 years, starting at age 30-35 years; consider hysterectomy after age 50 years

Upper Urinary Tract*

Urine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family

Urine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family

Stomach

Gastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family

Gastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family

Stage

Tumor

Node

Metastasis

Dukes

Stage 1

T1

N0

M0

Dukes A

T2

N0

M0

Stage II

T3

N0

M0

Dukes B

T4

N0

M0

Stage III

Any T

N1

M0

Dukes C

Any T

N2, N3

Mo

Stage IV

Any T

Any N

M1

Dukes D

Juan Carlos Munoz, MD Associate Professor of Medicine and Director of the Endoscopy Unit, Division of Gastroenterology, University of Florida College of Medicine at Jacksonville

Juan Carlos Munoz, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Louis R Lambiase, MD, MHA Professor of Medicine, University of Tennessee College of Medicine Chattanooga; Chief, Division of Gastroenterology, University of Tennessee Chattanooga Unit; Assistant Dean for Clinical Affairs, University of Tennessee College of Medicine Chattanooga

Louis R Lambiase, MD, MHA is a member of the following medical societies: American Gastroenterological Association, American Pancreatic Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Simmy Bank, MD Chair, Professor, Department of Internal Medicine, Division of Gastroenterology, Long Island Jewish Hospital, Albert Einstein College of Medicine

Disclosure: Nothing to disclose.

Hereditary Nonpolyposis Colorectal Cancer

Research & References of Hereditary Nonpolyposis Colorectal Cancer|A&C Accounting And Tax Services
Source

Share on Facebook

Tweet

Follow us